title: Inhibitors of retinyl ester formation also prevent the biosynthesis of 11-cis-retinol.
abstract: Lecithin retinol acyl transferase (LRAT) from the retinyl pigment epithelium is potently inhibited by all-trans-retinyl alpha-bromoacetate in the micromolar range. The inhibition is competitive and reversible. The retinyl pigment epithelium also contains an enzymatic activity capable of converting added all-trans-retinol into 11-cis-retinol. This isomerization is likely to require the intermediate formation of all-trans-retinyl esters, which are themselves produced by LRAT action. Here this possibility is directly tested by studying the effect of all-trans-retinyl alpha-bromoacetate on the isomerization reaction. When pigment epithelium membranes are preincubated with all-trans-retinyl alpha-bromoacetate, they form neither retinyl esters nor 11-cis-retinol from added all-trans-retinol. However, if the pigment epithelium membranes are first allowed to form all-trans-retinyl esters from all-trans-retinol before the addition of all-trans-retinyl alpha-bromoacetate, then 11-cis-retinol formation proceeds at close to the rate found in the absence of inhibitor. In addition, 11-cis-retinyl esters are not formed under these conditions, eliminating the possibility of a direct ester-ester isomerization route. Therefore, all-trans-retinyl esters are obligate intermediates in the biosynthesis of 11-cis-retinol.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: A
authors.initials: A
authors.lastname: Trehan
authors.forename: F J
authors.initials: FJ
authors.lastname: Cañada
authors.forename: R R
authors.initials: RR
authors.lastname: Rando
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002417:Cattle; D004224:Diterpenes / Q000494:pharmacology; D004952:Esters / Q000378:metabolism; D007536:Isomerism; D010857:Pigment Epithelium of Eye / Q000201:enzymology*; D000084562:Retinyl Esters; D014801:Vitamin A / Q000096:biosynthesis* / Q000378:metabolism*
chemical_list: D004224:Diterpenes; D004952:Esters; D000084562:Retinyl Esters; D014801:Vitamin A; C034831:retinyl bromoacetate; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase; D002265:Carboxylic Ester Hydrolases; C022523:retinyl esterase